Dopamine (DA) and DA depletion have been implicated in cortical function and in neurological disorders. The motor cortex receives a dense dopaminergic innervation and selective changes in DA distribution occur in Parkinson's patients. This proposal is designed to examine the morphological characteristics of the dopaminergic innervation of the motor cortex and to assess DA receptor regulation in response to DA depletion. Our preliminary studies have shown that DA innervation to the cat motor cortex is similar to that in humans. The pattern of DA distribution in the cat motor cortex will be examined. Immunohistochemical markers for DA will be used to examine the patterns of DA input. Features of DA innervation to the cortex suggest that intrinsic neurons are targets of DA axons and may be modulated by DA. One aim of the proposal is to determine the synaptic relationships of DA axons with identified target neurons whose projections are intrinsic to the motor cortex. Dual immunolabeling for DA axons and parvalbumin and calbindin containing neurons, will be done at the light and electron microscope levels to examine DA input to these 2 subpopulations of intrinsic GABAergic neurons. The pyramidal tract system appears to be involved in dopaminergic modulation of cortical function. Another aim is to determine the synaptic relationships of DA afferents and pyramidal tract neurons (PTNs) of the motor cortex. Dual labeling for dopaminergic axons and for retrogradely labeled PTNs will be done to examine DA distribution and synaptic connectivity onto these neurons at the light and electron microscope level. The final aim is to determine the distribution pattern and density of DA receptor subtypes in the motor cortex and the effects of DA depletion on DA receptor regulation in the motor cortex. Two receptor subtypes have been identified in the motor cortex and supersensitivity of one or both of these receptors is thought to delay the onset o motor symptoms in Parkinson's patients. Pharmacological treatment to selectively reverse upregulation of D1 or D2 receptors will be performed in DA depleted animals. The morphological characteristics of D1 and D2 receptor distribution and alterations in distribution following DA depletion and drug treatment will be examined. A quantitative analysis of the density of D1 and D2 receptors in the normal, DA depleted, treated and untreated animals will be done at the EM level. The morphological characteristics and the synaptic relationships of the DA innervation to the motor cortex will help to understand the mechanisms of DA function in cortical information processing, and of DA depletion in disease processes.